Transdermal administration preparation of a 9-aminocyclopenta (b) quinoline

ABSTRACT

A transdermal administration preparation containing a 9-aminocyclopenta(b)quinoline, preferably 9-amino-2, 3,5,6,7,8-hexahydro-1H-cyclopentane(b)quinoline or its hydrochloride, as an active ingredient and the following transdermal absorption enhancer, that is, at least one compound selected from the group consisting of fatty acids, fatty acid esters, and alcohols, preferably the glyceride of a saturated fatty acid having 6 to 12 carbon atoms.

This application is a 371 of PCT/JP95/02183, filed Oct. 24, 1995.

TECHNICAL FIELD

The present invention relates to a transdermal administrationpreparation, more specifically a transdermal administration preparationcontaining a 9-amino-cyclopenta(b)quinoline as an active ingredient.

BACKGROUND ARTS

9-aminocyclopenta(b)quinolines, in particular,9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline or its salts, asdisclosed in Japanese Examined Patent Publication (Kokoku) No. 63-35611and Japanese Examined Patent Publication (Kokoku) No. 3-54922, arecompounds useful as medicines for the treatment of Alzheinier's diseaseand other dementia and as medicines for the treatment of peripheralnerve-muscle transmission disorders. It is described that thesecompounds are to be administered to patients orally or by injection etc.to achieve the desired pharmaceutical effects.

Japan has experienced a sharp rise in diseases peculiar to the agedalong with the rapid aging of its population. In particular, seniledementia, especially Alzheimer's disease, have as major symptomsimpairment of memory, disorientation, dyslogia, etc. In addition, manypatients exhibit abnormal behavior such as poriomania. Further, someexhibit symptoms such as hallucinations or delusions. Therefore, theburden on the family members or medical personnel caring for them ishigh. Measures against this are becoming an important national issue.

Patients suffering from dementia, however, are unable in practice tocontrol the frequency or amount of ingestion of a drug on their ownvolition even looking at a single administration of a drug. Further,even if a doctor or family member instructs the patients to take themedication, they often cannot understand the instructions or else willnot follow the instructions even if understanding them. This is a majorhurdle in treatment. Further, the aged generally have reduced swallowingpower and, therefore, quite a few patients complain of suffering wheningesting solids such as tablets.

In this way, in patients suffering from senile dementia, oraladministration of a drug often becomes difficult along with theprogression of the disease. In this case, normally the drug isadministered by non-oral methods, that is, injection etc., but in thiscase it is essential that this be done by a doctor or other expert. Ontop of this, patients suffering from senile dementia differ from otherpatients in that there are a large number of patients fared for at homewhere trips to the hospital are difficult, therefore it is becomingurgent to find a method of administration of drugs effective for thesepatients as well.

In view of this situation, in recent years, the transdermal method ofadministration has been studied in the field of dementia. For example,Japanese Unexamined Patent Publication (Kokai) No. 61-186317 andJapanese Unexamined Patent Publication (Kokai) No. 4-338325 proposetransdermal administration preparations containing as an activeingredient tetrahydroaminoacridine etc. known as an antidementia drug.

That is, Japanese Unexamined Patent Publication (Kokai) No. 61-186317discloses a transdermal absorption preparation composition (fortreatment of dementia) comprising a basic drug composed of a combinationof a cholinergic agent or anticholinergic agent and a low molecularweight fatty acid.

Further, Japanese Unexamined Patent Publication (Kokai) No. 4-338325discloses a transdermal absorption preparation of a two-layer compositelaminate comprising a silicone elastomer and a large-pore polyethyleneslab and containing tetrahydroaminoacridine etc. as a drug.

However, these known preparations have the defects that thetetrahydroaminoacridine used as the active ingredient has strong sideeffects on the liver and further the frequency of occurrence of theseside effects is extremely high, therefore cannot be safety used forpatients suffering from dementia. No satisfactory therapeutic agent, hasyet been found.

DISCLOSURE OF INVENTION

In view of the above situation, the present inventors engaged in variousstudies to develop a practical and safe antidementia drug of atransdermal administration type and, as a result, found that a9-aminocyclopenta(b)quinoline, in particular,9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline, has anextremely superior action against dementia and is extremely high insafety with only very slight side-effects. They further engaged indetailed studies on the absorption from the skin (skin permeation) and,as a result, found that these drugs surprisingly are absorbed to acertain extent even transdermally and further if joint use is made of aspecific transdermal absorption enhancer, a concentration in the bloodof a level sufficient for exhibiting a pharmaceutical effect as a drugfor treating dementia is obtained, whereby the present invention hasbeen completed.

Accordingly, the main object of the present invention is to provide atransdermal administration preparation containing a9-aminocyclopenta(b)quinoline as an active ingredient.

Another object of the present invention is to provide a transdermaladministration type antidementia drug containing a 9-aminocyclopenta(b)quinoline and a transdermal absorption enhancer.

A further object of the present invention is to provide a safe andpractical transdermal absorption type antidementia drug.

Other objects of the present invention will become clearer from thefollowing explanation in this description.

In accordance with the present invention, there is provided atransdermal administration preparation comprising a9-amitiocyclopenta(b)quinoline, as an active ingredient, and atransdermal absorption enhancer formulated in an external base(composition).

BEST MODE FOR CARRYING OUT THE INVENTION

The preferable 9-aminocyclopenta(b)quinoline to be used as the activeingredient in the present invention is9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline of a structurewith a hydrated skeleton portion or a compound of this compound with the1-position and/or 8-position substituted with a hydroxyl group.Particularly preferred is9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline or itspharmaceutically acceptable salt. As the salt, a hydrochloride, sulfate,phosphate, fumarate, succiniate, or other pharmaceutically acceptableinorganic acid salt or organic acid salt is used, among which, ahydrochloride and its hydrate, for example, in the case of a9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline, a hydrochloridemonohydrate is preferred.

The amounts of the active ingredient (drug) contained in the preparationneed be only an amount sufficient for manifesting the desiredpharmaceutical effect. It differs according to the administeredpreparation, the type and amount used of the transdermal absorptionenhancer, the type of the drug used, etc., but normally a contentequivalent to 1 to 30% by weight in the preparation is used. In atransdermal administration preparation, generally the higher theconcentration (amount of use) of the drug in the preparation, thegreater the amount of permeation through the skein that can be expected.The residual amount of the drug in the preparation after use of thepreparation, however, increases in proportion to this, and therefore, acontent (amount of use) of the drug in the transdermal absorptionpreparation in the range described above is preferred.

As the transdermal absorption enhancer, a fatty acid, fatty acid ester,alcohol, etc. may be used.

As the fatty acid usable as the transdermal absorption agent, asaturated or unsaturated fatty acid having 12 to 18 carbon atoms, forexample, lauric acid, myristic acid, oleic acid, etc. is preferred. Forexample, a fatty acid having a small number of carbon atoms, for example1 to 4 carbon atoms, is not suitable due to the stench and skinirritation caused.

As the fatty acid ester usable as the transdermal absorption agent, amedium chain fatty acid glyceride or medium chain fatty acid glycolmonoester (e.g., ethylene glycol monocaprylate, propylene glycolmonocaprylate, etc.) is preferred, among which, a saturated fatty acidmonoglyceride having 6 to 12 carbon atoms, for example, caprylic acidmonoglyceride, capric acid monoglyceride, lauric acid monoglyceride,etc. are particularly preferred. These saturated fatty acidmonoglycerides can be easily available from the commercial products,such as "Stinsoft 700P-2" (caprylic acid monoglyceride, product of TaiyoKagaku K.K.)

As the alcohol usable as the transdermal absorption agent, a saturatedor unsaturated alcohol having 4 to 12 carbon atoms, for example, octylalcohol, lauryl alcohol, etc. is preferred.

The amount of the transdermal absorption enhancer contained in thepreparation is not necessarily fixed due to the different types ofexternal bases used, but normally is in the range of 1 to 50% by weight.

Further, these transdermal absorption enhancers may be used in anyappropriate mixture thereof, if necessary.

In addition, in the present invention, as solution adjuvants, ethanol,propanol, and other lower alcohols may be used.

As explained above, in the transdermal administration preparation of thepresent invention, combined use of the active ingredient and atransdermal absorption enhancer enables an extremely advantageous effectto be obtained, but in the specific application for a preparation, it ispossible to select from any of various forms of preparations expected togive a pharmaceutical effect by transdermal absorption depending uponthe purpose, for example, an ointment preparation, cream preparation,gel preparation, cataplasma preparation, plaster preparation (tapepreparation, patch preparation, etc.), use an external base and otheradditives suited to the desired preparation, and prepare the same by anordinary method, for example, a method described in the generalprovisions of preparations of the 12th edition of the Japan Pharmacopeiaso as to make various forms of preparations.

In the present invention, as the external base for blending the activeingredient and the transdermal absorption accelerator, a substancenormally meeting the requirements of the form of the preparation aimedat may be used, but basically the known substances usually used assubstrates for these preparations in the past are used.

For example, in the case of an ointment preparation, the substrate usedmay be vaseline, oleaginous ointment base, a lanolin and also an animalor plant oil, natural wax, other wax, or hydrates of the same.

Further, when adjustment of the viscosity is required, liquid paraffin,paraffin wax, microcrystalline wax, etc. may be suitably used.

In the case of a cream preparation, the base used is a vaseline, anester, triglyceride, straight (chain higher alcohol (cetanol, stearylalcohol, etc. of a chain length of 14 to 18 carbons or so) etc. In thiscase, the emulsification and physical stability may be maintained byfurther using a non-ionic surfactant, for example, a sorbitan fatty acidester, sorbitol fatty acid ester, polyoxyethylene fatty acid ester,polyoxyethylene alkyl ether, polyoxyethylene hardened castor oilderivative, polyoxyethylene potyoxypropylene alkyl ether, etc. in thecase of a gel preparation, the base used for an oil-based gel and anaqueous gel differ, balt in the case of an oil-based gel, a liquid oil(including hydrocarbons and esters) is gelated using magnesium stearate,a fatty acid dextran ester, or other gelation agent. In the case of anaqueous gel, a carboxyvinyl polymer, hydroxypropylcellulose, polyvinylalcohol, aluminum hydroxide, bentonite, or other gelation agent may beused.

In the case of a cataplasma preparation, the substrate used may begelatin, sodium polyacrylate, polyvinyl alcohol, orpolyvinylpyrrolidone.

In the case of a plaster preparation, in the case of either a tapepreparation or a patch preparation, the base used may be a naturalrubber, synthetic isoprene rubber, or other rubber family adhesive orpolyacrylate ester or other polymer acrylic family adhesive anddimethylsiloxane and other silicone family adhesive etc. comprised ofpolymers. Further, polyethylene terephthalate film is used as a support.

As explained above, in the transdermal administration preparation of thepresent invention, it is possible to use various substances as theexternal base, but it is also possible to suitably add into thepreparations, when needed, arabia gum, lecithin, glycerin, propyleneglycol, and other emulsifiers, suspension agents, humectants, and otheradditives.

The transdermal administration preparation of the present invention thusprepared is administered to patients according to ordinary methods inaccordance with these forms. The dosage is the same as in the past anddepends on the form etc., but in general is about 1 to 1,000 mg/dayactive ingredient for adults.

EXAMPLES

The present invention will now be explained in further detail withreference to Examples, but the present invention is not limited to theseExamples and various modifications are possible. Further, in thefollowing Examples and Test Examples, the drug (active ingredient) used,unless specialty otherwise mentioned, was all9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline hydrochloridemonohydrate (9ACQ).

Example 1 (Aqueous Gel Preparation)

0.8 g of hydroxypropylcellulose was added to and dissolved in 20 ml of40% by weight ethanol. 1 g of caprylic acid monoglyceride and 6 g of adrug (9ACQ) were added to this and stirred well. The mixture was allowedto stand over night in a refrigerator to obtain a aqueous gelpreparation.

Example 2 (Cream Preparation)

The ingredients other than the drug and purified water were mixedaccording to the following formulation. The drug was dissolved in thepurified water and added into the mixture which was then stirred andemulsified to obtain a cream preparation.

    ______________________________________    9ACQ               1 g    White vaseline     15 g    Liquid paraffin    5 g    Cetanol            5 g    Stearyl alcohol    5 g    Polyoxyethylene cetyl ether                       5 g    Oleic acid         10 g    Purified water     q.s.    Total              100 g    ______________________________________

Example 3 (Cataplasma Preparation)

The gelatin and purified water were mixed according to the followingformulation and then warmed to 70° C. to dissolve the gelatin. A mixtureof the zinc oxide, glycerol, sorbitol, and lauryl alcohol was added tothe solution which was then mixed well.

Next, sodium polyacrylate and sodium carboxymethylcellulose were addedwith vigorous stirring. A mixture of the menthol, camphor, and drug wasthen added to this mixture.

The resultant mixture was kneaded well and spread over a nonwovenfabric. The surface of the ointment was covered by a polyethylene film.The resultant product was cut into suitable sizes to obtain cataplasmapreparations.

    ______________________________________    9ACQ                 1 g    Gelatin             10 g    Zinc oxide          10 g    Glycerol            10 g    Sorbitol            10 g    Lauric alcohol      10 g    Sodium polyacrylate  5 g    Sodium carboxymethylcellulose                         5 g    Menthol              2 g    Camphor              1 g    Purified water      q.s.    Total               100 g    ______________________________________

Example 4 (Ointment Preparation)

White vaseline, stearyl alcohol, polyoxyethylene hydrogenated castor oil60, glycerol monostearate, and oleic acid were taken according to thefollowing formulation, mixed on a water bath, heated to dissolve, andheld at about 75° C. (Solution 1). Separately, methyl para-oxybenzoate,propyl para-oxybenzoate, and propylene glycol were mixed, then purifiedwater was added and the resultant mixture warmed to about 75° C.(solution 2) and the drug was dissolved in warmed purified water(solution 3).

The solution 2 and solution 3 were gradually added to the solution 1with stirring, then the warming was stopped. The stirring was continueduntil solidifying to obtain the ointment preparation.

    ______________________________________    9ACQ                   1 g    White vaseline        25 g    Stearyl alcohol       20 g    Propylene glycol      12 g    Polyoxyethylene hardened castor oil 60                           4 g    Glycerol monostearate  1 g    Methyl para-oxybenzoate                          0.1 g    Propyl para-oxybenzoate                          0.1 g    Oleic acid             5 g    Purified water        q.s.    Total                 100 g    ______________________________________

Example 5 (Tape Preparation)

1 g of a drug (9ACQ) and 5 g of an acrylic adhesive Polysic 310-S(commercial product of Sanyo Kasei Kogyo) were added to 3 ml of ethylacetate and stirred well (solution 1). Further, 0.03 g of thecross-linking agent isophorone isocyanate was dissolved in 0.5 ml ethylacetate (solution 2). 3 g of caprylic acid monoglyceride was suspendedin 6 ml of ethyl acetate (solution 3). Solution 2 and solution 3 weremixed into solution 1 and stirred well to obtain a viscous solution.This solution was coated on a substrate (polyethylene terephthalate(PET) film) to give a thickness of about 60 microns and then dried toobtain a tape preparation.

Test Example 1

The preparation (sample F) obtained in the above Example 1 and thesamples prepared as explained below were tested for skin permeationusing skin excised from the abdomen of hairless rats (male, body weightof 220 g to 250 g).

Preparation of Samples

The samples used in the test, except those obtained from the aboveExamples, were prepared by the following methods:

Sample A: 1.2 g of 9ACQ and 0.3 g of caprylic acid monoglyceride wereplaced in 6 ml of water and stirred well to obtain a preparation.

Sample B: 1.2 g of 9ACQ and 0.3 g of capric acid monoglyceride wereplaced in 6 ml of water and stirred well to obtain a preparation.

Sample C: 1.2 g of 9ACQ was placed in 6 ml of water and stirred well toobtain a preparation.

Sample D: 1.4 g of tetrahydroaminoacridine hydrochloride (THA) and 0.3 gof caprylic acid monoglyceride were placed in 6 ml of water and stirredwell to obtain a preparation.

Sample E: 1.4 g of THA was placed in 6 ml of water and stirred well toobtain a preparation.

Sample G: 0.8 g of hydroxypropylcellulose was added to and dissolved in20 ml of 40% ethanol. 6 g of 9ACQ was added to this mixture and themixture was stirred well. The mixture was allowed to stand overnight ina refrigerator to obtain a water-based gel preparation.

Test Method

The test was carried out using a 2-chamber diffusion cell of theflow-through type (effective area of 1 cm² and volume of 2.5 ml),setting different preparations at the donor side (stratum corneum layerside), placing normal saline at the receiver side, quantizing the amountof the drug moving from the samples (preparations) through the skin tothe receiver side by high pressure liquid chromatography, and findingthe skin permeation rates based on the same. The results are shown inTable 1.

                  TABLE 1    ______________________________________    Skin Permeation of Various Preparations                                      Skin                                      permeation                       Composition of rate*    Sample    Drug     preparation    (μg/cm.sup.2 /hr)    ______________________________________    Invention    A         9ACQ     Caprylic acid  2155 ± 434                       monoglyceride, water    B         9ACQ     Capric acid    1912 ± 768                       monoglyceride, water    Control    C         9ACQ     Water           35 ± 11    D         THA      Caprylic acid   37 ± 15                       monoglyceride, water    E         THA      Water           3 ± 2    Invention    F         9ACQ     40% ethanol, caprylic                                      5254 ± 575                       acid monoglyceride,                       hydroxypropylcellulose    Control    G         9ACQ     40% ethanol,   12 ± 2                       hydroxypropylcellulose    ______________________________________

Test Example 2

The preparation (sample F) obtained in the above Example 1 and thesample G prepared in Test Example 1 were tested for in vivo skinpermeation in hairless rats according to the following test method.

Test Method

The chest portions of hairless rats were shorn and various samplesapplied. The area of administration of the samples was 1 cm² and thedosage was 2.8 g. The blood was sampled 2, 4, 6, 8, and 24 hours afteradherence. The drug was extracted from the serum and was quantized bythe CGC/MS method to find the concentration in the blood. The resultsare shown in Table 2.

                  TABLE 2    ______________________________________    In Vivo Skin Permeation in Hairless Rats    Adherence time  Concentration in blood (ng/ml)    (hr)            Ex. 1     Sample G    ______________________________________    2               192 ± 51                              35 ± 6    4               924 ± 413                               64 ± 19    6               2943 ± 1006                              101 ± 34    8               3796 ± 965                              138 ± 58    24                         34 ± 16    ______________________________________     *Figures are shown as mean values ± S.E. of four examples.

Test Example 3

The samples prepared as described below were tested by methods similarto those of Test Example 1. The results are shown in Table 3.

Sample H: 1.2 g of 9ACQ and 0.3 g of lauric acid were placed in 6 g of40% by weight ethanol and stirred well to obtain a preparation.

Sample I: The same procedure as the method of preparation of sample Hwas followed to obtain a preparation except that the lauric acid wasmade oleic acid.

Sample J: The same procedure as the method of preparation of sample Hwas followed to obtain a preparation except that the lauric acid wasmade octanol.

Sample K: 2.4 g of 9ACQ and 0.3 g of caprylic acid monoglyceride wereplaced in 6 g of 40% by weight ethanol and stirred well to obtain apreparation.

Sample L: 1.2 g of 9ACQ was placed in 6 g of 40% by weight ethanol andstirred well to obtain a preparation.

Sample M: 2.4 g of THA and 0.3 g of caprylic acid monoglyceride wereinserted into 6 g of 40% by weight ethanol and stirred well to obtain apreparation.

                  TABLE 3    ______________________________________    Skin Permeation of Various Preparations                                    Skin                                    permeation                     Composition of rate*    Sample  Drug     preparation    (μg/cm.sup.2 /hr)    ______________________________________    Invention    H       9ACQ     Lauric acid, 40%                                    9776 ± 83                     ethanol    I       9ACQ     Oleic acid, 40% ethanol                                    6287 ± 198    J       9ACQ     Octanol, 40% ethanol                                    9686 ± 505                     Caprylic acid    K       9ACQ     monoglyceride, 40%                                    18212 ± 2477                     ethanol    Control    L       9ACQ     40% ethanol     59 ± 29    M       THA      Caprylic acid  293 ± 57                     monoglyceride, 40%                     ethanol    ______________________________________     *Figures are shown as mean value ± S.E. of three examples.

INDUSTRIAL AVAILABILITY

According to the transdermal administration preparation of the presentinvention, it is possible for a care-giver to easily administer a drugto a patient suffering from dementia and further the requiredconcentration of the drug administered in the blood is maintained over along period, and therefore, present invention is extremely useful forpatients suffering from dementia for which administration of drugs isdifficult.

We claim:
 1. A transdermal administration preparation comprising from 1to 30% by weight of a 9-aminocyclopenta(b)quinoline or apharmaceutically acceptable salt thereof as an active ingredient and atleast one transdermal absorption enhancer selected from the groupconsisting of fatty acids, fatty acid esters and alcohols.
 2. Atransdermal administration preparation as claimed in claim 1, whereinthe active ingredient is9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline or itspharmaceutically acceptable salt.
 3. A transdermal administrationpreparation as claimed in claim 2, wherein the active ingredient is9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta(b)quinoline hydrochloridemonohydrate.
 4. A transdermal administration preparation as claimed inany one of claims 1-3, wherein the transdermal absorption enchancer is afatty acid.
 5. A transdermal administration preparation as claimed inclaim 4, wherein the fatty acid is a saturated or unsaturated fatty acidhaving 12 to 18 carbon atoms.
 6. A transdermal administrationpreparation as claimed in any one of claims 1-3, wherein the transdermalabsorption enhancer is a fatty acid ester.
 7. A transdermaladministration preparation as claimed in claim 6, wherein the fatty acidester is a glyceride of a medium chain fatty acid.
 8. A transdermaladministration preparation as claimed in claim 7, wherein the glycerideof the medium chain fatty acid is a monoglyceride of a saturated fattyacid having 6 to 12 carbon atoms.
 9. A transdermal administrationpreparation as claimed in any one of claims 1-3, wherein the transdermalabsorption enhancer is an alcohol.
 10. A transdermal administrationpreparation as claimed in claim 9, wherein the alcohol is a saturated orunsaturated alcohol having 4 to 12 carbon atoms.
 11. A transdermaladministration preparation as claimed in any one of claims 1 to 3,wherein the transdermal administration preparation is one form selectedfrom the group consisting of an ointment, cream, gel, and cataplasmapreparation.
 12. A transdermal administration preparation as claimed inany one of claims 1 to 3, wherein the transdermal administrationpreparation is a tape or patch preparation.